CHOP THERAPY INDUCED MITOCHONDRIAL REDOX STATE ALTERATION IN NON-HODGKIN'S LYMPHOMA XENOGRAFTS.

H N Xu,S C Lee,L Z Li,L Z Li,T A Mir,L Z Li,J D Glickson,M Feng,M Feng,H Zhao,L Z Li,R Choe,T A Mir

doi:10.1142/s1793545813500119

Abstract

We are interested in investigating whether cancer therapy may alter the mitochondrial redox state in cancer cells to inhibit their growth and survival. The redox state can be imaged by the redox scanner that collects the fluorescence signals from both the oxidized-flavoproteins (Fp) and the reduced form of nicotinamide adenine dinucleotide (NADH) in snap-frozen tissues and has been previously employed to study tumor aggressiveness and treatment responses. Here, with the redox scanner we investigated the effects of chemotherapy on mouse xenografts of a human diffuse large B-cell lymphoma cell line (DLCL2). The mice were treated with CHOP therapy, i.e., cyclophosphamide (C) + hydroxydoxorubicin (H) + Oncovin (O) + prednisone (P) with CHO administration on day 1 and prednisone administration on days 1-5. The Fp content of the treated group was significantly decreased (p = 0.033) on day 5, and the mitochondrial redox state of the treated group was slightly more reduced than that of the control group (p = 0.048). The decrease of the Fp heterogeneity (measured by the mean standard deviation) had a border-line statistical significance (p = 0.071). The result suggests that the mitochondrial metabolism of lymphoma cells was slightly suppressed and the lymphomas became less aggressive after the CHOP therapy.

Highlights

Redox scanning is an ex vivo optical imaging method that can be applied to image the 3D tissue mitochondrial redox state with sub-millimeter high resolution based on the °uorescence signals of the endogenous NADH and Fp.[1,2] Mitochondrial NADH is the main source of the reducing equivalents for the mitochondrial respiratory chain
Mitochondrial metabolism is re°ected in the redox state of the NAD system, which is tightly coupled with the °avin redox state in °avoproteins
We present our initial redox scanning results on CHOP-treated DLCL2 xenografts in mice[10] and demonstrate that the redox scanning has the potential to detect therapeutic e®ects on cellular metabolism in Non-Hodgkin's lymphoma (NHL)

Summary

Introduction

Redox scanning is an ex vivo optical imaging method that can be applied to image the 3D tissue mitochondrial redox state with sub-millimeter high resolution based on the °uorescence signals of the endogenous NADH and Fp (including °avin adenine dinucleotide, i.e., FAD).[1,2] Mitochondrial NADH is the main source of the reducing equivalents for the mitochondrial respiratory chain. The redox ratios, i.e., Fp/NADH, NADH/Fp, and Fp/(FpþNADH), have been shown as sensitive biomarkers for the mitochondrial metabolic state. The redox scanning indices have been shown to di®erentiate between an indolent and a metastatic breast cancer in mouse xenografts.[3] The tumor redox ratios correlated signicantly with the invasive potentials ofve melanoma lines xenografted in mice.[4] The redox scanning showed increased heterogeneity in the mitochondrial redox state in the pre-malignant mouse pancreases,[5] and used to detect the metabolic changes in a glioma rat model under photodynamic therapy.[6] the redox scanning has been employed to measure the cyclophosphamide-treatment e®ect on RIF-1 tumors in mice.[7] the redox scanning has not been applied to study the metabolic alterations in lymphomas subjected to CHOP treatment

Methods

Results

Conclusion